tbuckley/cabot-search huggingface dataset:
Abstract P3022: Smyd2 Deficiency Protects Against Atherosclerotic Plaque Formation Through Modulation Of Oxidative Stress
Authors: Shaligram Sharma, Xiaoqing Guan, Yuning Hou, Jada Harvey, Pranav Lamba, Jacob Li, Arin Dorsey, Kotryna Diktonaite, Chunying Li
Journal: Circulation Research (2023)

Introduction: Oxidative stress induced vascular remodeling promotes atherosclerosis. By scavenging excessive ROS levels, NRF2 protects vascular cells against oxidative stress and exerts anti-inflammatory activity through modulation of HO-1. This study aimed to explore smooth muscle cell (SMC)-specific role of SMYD2 in modulating atherosclerosis associated oxidative stress in vivo and in vitro . Methods: SMC-specific SMYD2 knockout mice in ApoE -/- background (SMYD2 ΔSMC ApoE -/- ) and their littermate controls (SMYD2 fl/fl ApoE -/- ) were subjected to Western diet feeding for 18-26 weeks. Atherosclerotic plaque distribution was examined by en-face Oil Red O (ORO) staining of aortas from both groups. Hematoxylin &amp; Eosin (H&amp;E) staining on brachiocephalic artery tissues were performed to determine atherosclerotic plaque burden by measurements of total plaque size, lipid pool area, and necrotic core area. Lipid peroxidation was analyzed in aortic tissues and in blood serum. Primary VSMCs isolated from control and SMYD2 depleted mice and cultured C3H/ 10T1 / 2 cells were used for in vitro studies. Results: SMC-specific SMYD2 depletion attenuated atherosclerotic plaque establishment and progression. En -face ORO analysis revealed significant suppression of ORO positive areas in SMYD2 ΔSMC ApoE -/- mice compared to control mice. H&amp;E analysis of lesions showed significant reduction of total plaque size, despite accumulation of lipids, in SMYD2 ΔSMC ApoE -/- mice as compared to control mice. Immunofluorescence staining of aortic tissues showed increased expression of NRF2, HO-1 and GPX4 in SMYD2 ΔSMC ApoE -/- mice compared to controls, as observed in serum by MDA assay. Mechanistic studies using C3H/ 10T1 / 2 cells treated with PAz-PC (oxLDL), GPX4 inhibitor, with or without SMYD2 knockout, demonstrated that SMYD2 modulates HO-1 and GPX4 expression through NRF2. Specifically, SMYD2 binds NRF2 and reduces its translocation into the nucleus, thereby repressing HO-1 expression and inducing oxidative stress. Conclusion: SMYD2 depletion induces atheroprotective effect via reducing plaque burden and promoting antioxidant activity of NRF2/HO-1 axis, suggesting SMYD2 could be a therapeutic target against atherosclerosis.
Abstract P3159: Exosomes Derived From Podoplanin Positive Cells Induce Endo-Mt And Myofibroblast Transformation In Healthy Mouse Heart And After Ischemic Injury
Authors: Maria Cimini, Vandana Mallaredy, Conchi Estaras, May Truongcao, Chunlin Wang, Cindy Benedict, Raj Kishore
Journal: Circulation Research (2023)

Specific understanding of the differences in cell communications between physiologicaland pathological conditions harbor the understanding of mechanisms to recover theequilibrium in the injured tissue and restore the organ function. Neurohumoral factorsreleased after myocardial infarction (MI) induce the expression of platelet aggregation-inducing type I transmembrane glycoprotein named Podoplanin (PDPN) in mesenchymalstromal cells, which pivot their structural support function and actively participate in theremodeling of the ischemic tissue releasing an abundance of extracellular vesicles calledexosomes. Exosomes (exo) derived from activated PDPN+ cells conditioned media wereused in vivo for the treatment of healthy mouse hearts, and in vitro for the treatment ofmouse cardiac endothelial cells (mCECs), NHI-3T3 and adult cardiac fibroblast. Ourongoing experiments showed that in vivo, PDPN-exo could independently alter healthyheart physiology and structure; mice hearts treated with PDPN-exo developed anextended epicardial fibrosis with a subsequent impairment in the contractility and increaseof the end diastolic and systolic volumes. The fibrotic area was characterized by ECMdeposition, increased lymphatic vessels and infiltrating CD45+ cells. In vitro, PDPN-exoreprogramed mCECs, NHI-3T3 and adult cardiac fibroblast, upregulating the expressionof fibrotic markers suggesting an Endothelial-Mesenchymal Transition (EndoMT) andmyofibroblast transformation. Proteomic analysis of PDPN-exo suggests these transitionsmay depend upon the delivery of NOTCH1 via exosomes and the cleavage of it throughγ-Secretase. Experiments of gain and loss of NOTCH1 function showed thatoverexpression of NOTCH1 intracellular domain (NICD1) in vitro was sufficient to derivea lineage switching in mCECs and fibroblasts on the contrary in vivo delivery and in vitrotreatment with exosomes derived from PDPN+ cells silenced for NOTCH1 or treatmentwith γ-Secretase inhibitor did not alter the heart structure and function or the endothelialcells and fibroblast lineage. Thus, NOTCH1 delivery via PDPN-exo after MI play a majorrole in scar remodeling and its biology can be pharmacologically modulated.
Abstract P1094: Mesenchymal Stem Cells Educate Lung Megakaryocytes To Favor Cardiac Repair Post Myocardial Infarction
Authors: Shiqi Hu, Ke Cheng
Journal: Circulation Research (2023)

Stem cell therapy in myocardial infarction (MI) have mixed clinical results, and the mechanism of its potential benefits is uncertain. Intravenously administrated mesenchymal stem cells (MSCs) are trapped in the lung capillary bed and hardly reach to the heart. Despite their extremely low retention in the heart, cardiac repair benefits are still seen in multiple clinical trials. There is a large knowledge gap exists regarding the interconnection and bidirectional pathways between heart and lung. It has been established that lung is a reservoir of megakaryocytes (MKs), which produce platelets. We found that MSCs trapped in the lung capillary altered the transcription profiles of lung MKs and circulating platelets. Single cell analysis revealed that MSCs reduced the activation of megakaryocyte progenitor cells (MKp) and promoted MK maturation in the lung. Additionally, MSC treatment reduced the activation of immune cells and the ratio of proinflammatory monocytes in the lung and macrophage infiltration in the infarcted area. CellChat analysis demonstrated that reduced communication between lymphocytes and MKp after MSC treatment. Lastly, we demonstrated that cell-cell contact was needed for this education process, and MSC secretome didn’t promote the megakaryopoiesis process in vitro and in vivo . Intravenously injection of MSCs showed a better therapeutic effect compared to MSC secretome in MI mice. Collectively, this study unevils the role of pulmonary MK in lung-heart crosstalk and the interaction of MSCs trapped in the lung tissue with pulmonary MK during MI. Scheme 1. Schematic illustration of heart-lung crosstalk and the role of lung MK during MI.
Abstract P1086: Induced Pluripotent Stem Cell-based Cardiac Tissue Modeling Of Mitogenic Cardiomyopathy In Alström Syndrome
Authors: Robin Duelen, Samaneh Ekhteraeitousi, Domiziana Costamagna, Ellen Caluwé, Hilde Gillijns, Johanna Jacobs, Ming Wu, Brigitte Malgrange, Koenraad Devriendt, Llewelyn Roderick, Jianyi J Zhang, Maurilio Sampaolesi, Stefan Janssens
Journal: Circulation Research (2023)

Introduction: Cardiomyopathies are a prominent cause of heart failure and affect millions worldwide. Mutation in the Alström syndrome 1 (ALMS1) gene causing Alström syndrome (ALMS) , reported an extremely rare type of dilated cardiomyopathy - called mitogenic cardiomyopathy - leading to neonatal heart failure and death in early infancy due to delayed postnatal cardiomyocyte (CM) cell cycle arrest. Methods: Induced pluripotent stem cells (iPSCs) from ALMS patients with or without mitogenic cardiomyopathy were used to generate ALMS patient-specific cardiomyocytes (iPSC-CMs) . The iPSC-CMs were divided into two main groups based on the presence or absence of the mitogenic phenotype. After transcriptome sequencing, differentially expressed genes (FDR &lt; 0.05, logFC &gt; 0.5 | &lt; -0.5) were found by testing (QL F-test) a robust fitted linear model (edgeR). Harnessing recent advances in stem cell differentiation and tissue engineering, we aimed at creating a human engineered heart tissue model as an unprecedented in vitro disease system to study mechanisms responsible for persistent CM proliferation. Results: ALMS1-deficient mitogenic iPSC-CMs exhibited an impaired ability to undergo cell cycle arrest, evidenced by a higher cell percentage in the G2/M phase (19.3% in mitogenic vs . 7.5% in non-mitogenic iPSC-CMs). Furthermore, increased extracellular matrix levels of the fibroblast-derived protein periostin (POSTN) were observed in co-cultures of ALMS1-deficient iPSC-CMs and ALMS1 fibroblasts. Finally, we found preliminary evidence of dysregulation of the Hippo signaling pathway, observing altered cellular localization of its key downstream effector Yes-associated protein (YAP) and dysregulated ratio between phosphor and total YAP protein levels that in combination with transcript alteration of PPIC, SH3BP4, NTN4, LRIG3 suggest perturbations in YAP signaling in ALMS patients. Conclusion: ALMS1-deficient mitogenic iPSC-CMs recapitulate postnatal proliferation, observed in ALMS patients with mitogenic cardiomyopathy. Preliminary molecular analyses in these in vitro (multicellular) models point to an important role for altered YAP signaling and provide novel cues to enhance CM proliferation, a much-sought objective in cardiac repair.
Abstract P2178: Trends In Age At Diagnosis, Incidence Proportion Of Benign Cardiac Neoplasms And Associated Outcomes: 2012-2021
Authors: Bharat Rawlley, Andres Cordova Sanchez, Sherna Menezes, Kartik Gupta, Debanik Chaudhuri
Journal: Circulation Research (2023)

Introduction: Incidence of benign cardiac neoplasms (BCNs) and outcomes in large scale studies among adults in US are unknown. We study this using TriNetX database. Methods: We queried TriNetX US Collaborative network housing data from insurance claims and electronic health records. We include adult patients with any ICD code from 01/01/12 - 12/31/21. ICD codes were used to identify BCN and ventricular arrhythmias, ischemic stroke and acute MI after BCN diagnosis. Mortality was identified by patients categorized as deceased after BCN diagnosis. Results: We identified 65.6 million patients (54% female), BCN prevalence was 0.0097% (n=6420). Mean (SD) age at diagnosis for males, females was 58.7 (18.2), 61.1 (17.5) years, respectively. Mean (SD) age at diagnosis increased from 57.2 (20.1) to 62.8 (16.9) years (P &lt; 0.05). Incidence proportion for BCN in females and males was 0.013% and 0.010% respectively, no trend was seen in annual incidence proportion for either sex (P &gt; 0.05). On comparing those with vs without BCN, BCN cases were at higher risk of mortality, Ventricular arrhythmia, Ischemic stroke, and acute MI with RR (95% CI); 3.56 (3.36-3.77), 11.9 (10.9-12.9), 10.09 (9.58-10.62) and 9.41 (8.84-10.02), respectively. The risk of mortality, ventricular arrhythmia, Acute MI and ischemic stroke in males vs females with BCN was 17.4% vs 15.3%, 4.6% vs 4.1%, 7.6% vs 9.2% and 7.5% vs 6.3%, respectively. Conclusion: Annual incidence proportion of BCNs remains stable from 2012-21. An increasing trend in age at BCN diagnosis is seen. Females have higher Incidence proportion and age at diagnosis. BCN patients are at risk of adverse outcomes with males having worse outcomes.
Abstract P3025: CXCL10 Impairs Endothelial Barrier Integrity In Endothelial Pparδ-deficient Mice Identified By Single-cell RNA Sequencing
Authors: Huiling Hong, Kevin Y Yang, Kathy O Lui, Xiao-Yu Tian
Journal: Circulation Research (2023)

Rationale and Background: CXCL10 is a pro-inflammatory chemokine produced by monocytes and endothelial cells (ECs) in response to IFNγ, acting as a chemoattractant for monocytes and T cells etc., through the CXCR3 receptor. The previous study from our group showed that selective deletion of PPARδ in the endothelium worsens ischemic vascular injury in mouse model of hindlimb ischemia. Single-cell RNA sequencing of muscle endothelial cells showed that PPARδ regulates genes involved in endothelial barrier function and vascular inflammatory responses. Methods and Results: To further understand the role of PPARδ in endothelial cells from different vascular beds, we induced acute lung inflammation by lipopolysaccharide (LPS) in EC-selective PPARδ knockout mice (Ppard EC-KO ) and their wild-type littermates (Ppard EC-WT ) and analyzed the lung ECs by scRNAseq. After LPS injection, lung ECs were collected as CD45 - CD31 + CD144 + cells by FACSorting, and scRNAseq was performed using 10X genomics method. General capillary ECs and aerocyte capillary ECs were identified by distinctive marker genes as the two most abundant lung ECs. The capillary ECs from LPS-challenged Ppard EC-KO mice showed high enrichment of inflammatory signaling including IFN-IRF, IL6-STAT3, and TNFα-NFκB. Further sub-clustering analysis revealed a capillary EC subset with upregulation of IFN signaling and identified CXCL10 as the top marker-gene in LPS-challenged mice. CXCL10 expression was indeed upregulated in the lung tissue of LPS-treated Ppard EC-KO mice and in TNFα-treated human lung microvascular endothelial cells (HLMVECs). CXCL10 decreased the expression of EC tight junctional proteins ZO-1 and Claudin-5 through the ubiquitin-proteosome system-mediated degradation in HLMVECs. Blocking the CXCR3 by AMG487 suppressed vascular leakage and EC activation in response to LPS. Conclusion: These results suggested the possibility of targeting CXCL10 signaling for restoring vascular homeostasis in acute lung inflammation. (Supported by Hong Kong Research Grant Council GRF 14107822 and 14105321)
Abstract P1087: Cd36-retinoic Acid-PPARδ Signaling Axis Modulates Cardiomyocytes’ Ability To Proliferate In Newly Born Neonatal Mice
Authors: Abou Bakr M Salama, Riham Abouleisa, Qinghui Ou, Jessica Miller, Marc Dwenger, Ahmad Gebreil, Hania abdelhafez, Momo Arai, Sameeha Abdulwali, yazan Almasry, Bradford G Hill, Tamer Mohamed
Journal: Circulation Research (2023)

Background: A pertinent question is why only a subset of fetal/neonatal cardiomyocytes (CMs) spontaneously proliferate. Using single-cell RNAseq, we previously showed a specific population of CMs that is more responsive to cell cycle induction (Abouleisa et al., Circulation, 2022). This population is characterized by expression of the transmembrane scavenger receptor, CD36 (fatty acid (FA) internalization receptor). Here, we aim to investigate the mechanism by which CD36 modulates CMs decision to enter into the cell cycle in neonatal P1 CMs. Methods and Results: Our single-cell RNAseq from primary CMs isolated from P1 hearts demonstrated that CD36 is specifically expressed in the spontaneously proliferating CMs and the CMs that respond to the exogenous cell cycle stimulation. CMs isolated from P1 CD36 knockout mice (CD36 KO ) showed 50% less proliferation capacity compared to WT P1 CMs. Interestingly, CD36 KO mice are born with smaller hearts which contain fewer CMs compared with their WT littermates. Furthermore, compared with WT littermates, which completely regenerate the heart apex following apical resection at P1, CD36 KO showed minimal regenerative capacity. Surprisingly, CD36 KO CMs didn’t show significant disruption in FA oxidation or glycolysis; however, bulk RNAseq data from the P1 CD36 KO hearts showed significant downregulation in the expression of retinoic acid (RA)-dependent signaling genes (e.g., PPARδ and RXRa) and a significant increase in PPARα expression. Confirming a causal role of CD36 in CM proliferation, we found that Cd36 is crucial in regulating the entry and interactions of RA or retinoid precursors in CMs. The CD36 + FACS-sorted CMs express significantly higher levels of PPARδ, RXRa, and FABP5 and lower levels of PPARα, which are crucial in regulating the response to cell proliferation. Furthermore, small molecule activation of PPARδ doubled cell cycle entry in P1 CMs and completely restored proliferation in CD36 KO CMs. These data suggest that CD36 is essential to prime CMs proliferation during development by regulating RA/PPARδ/RXR transcriptional signaling. Conclusions: These findings suggest that the CD36-RA-PPARδ signaling axis modulates the CMs’ ability of P1 to spontaneously enter the cell cycle.
Abstract P2173: Naltrindole Offers Potent Cardioprotection From Ischemia Reperfusion Injury; Opioid Antagonism Or Calcium Handling?
Authors: Desmond Boakye Tanoh, Sunit G Singh, Smith Frimpong, Arjun Nair, Tameka C Dean, Qian Chen, Robert Barsotti, Lindon H Young
Journal: Circulation Research (2023)

Coronary Artery Disease accounts for approximately 25% of deaths annually, and remains theleading cause of mortality inthe United States. Myocardial ischemic (MI) damage is the initialinjury, characterized by irreversible hyper-contracture of cardiac muscle. Currently, there is nopharmacologic treatment tomitigate MI damage that may occur inthe 250,000CABGs,215,000percutaneous coronary interventions (PCI), and heart transplantation. We havepreviously reported that naltrindole (NTI) dose-dependently reduces infarct size upto82% ininvivomyocardial ischemia-reperfusion(MI/R) studies whengivenprior toregional ischemia. Werecently have shownthat NTI elicits this robust infarct size reducing effect by anovelmechanism since NTI alsoreduces polymorphonuclear leukocyte (PMNs) superoxide (SO)release at concentrations corresponding tothe blood concentrationinthe invivoMI/R study(8mg/kg = ~200uM; 4mg/kg = ~100uM). PMNs donot express opioid receptors, and NTI isknowntobe adeltaopioid receptor antagonist.Inour ex vivoLangendorff rat MI/R model, male SD rats (~300g) were anesthetized, heartswere removed, perfused with 37°C Krebs’ buffer and apressure transducer was placed intheleft ventricle (LV). Baseline recordings were made during the first 10minand the hearts werepretreated with NTI (5uM, n=8), naloxone (NX; panopioid receptor antagonist; 10uM, n=6)and binaltorphimine (BNI; kappaopioid receptor antagonist, 5uM, n=7) or controls (n=12) for 5mins prior toglobal I(30min)/R(45min).Ischemic PeakPressure (IPP) incontrolI/R heartswas39±3mmHg comparedtopre-ischemicLVEDP of9±1mmHg atbaseline(n=12,p&lt;0.01),resultinginsubstantialinfarctatthe endof45minR (32±4%).IPP wasreduced byNTI (18±3mmHg/s)comparedtoallgroups(p&lt;0.05).FinaldP/dt maxandinfarctsize were mostimprovedwith NTI (1830±90mmHg/s, 7±2%)comparedtocontrol(777±142mmHg/s, 32±4%,p&lt;0.01).Cardiacfunctionandinfarctsize did notimprovewith BNI orNX. The resultssuggested that NTI exerted robust cardioprotectionwith significant reductionininfarct sizeindependent of deltaor kappaopioid receptor which led toinvestigating its possible underlyingmechanism of action.
Abstract P3140: Extracellular Vesicle MicroRNA Cargo Drives Ventricular Arrhythmia In Heart Failure Patients By Recapitulating Developmental Genes
Authors: Priyanka Gokulnath, Michail Spanos, Helge I. Lehmann, Quanhu Sheng, Ling Xiao, Nedyalka Valkov, Avash Das, Emeli Chatterjee, Guoping Li, Eric Alsop, Kendall Van Keuren-Jensen, Ravi V Shah, Saumya Das
Journal: Circulation Research (2023)

Heart Failure (HF) is the leading cause of death worldwide, of which arrhythmias account for 50%. The relationship between HF and arrhythmias is closely intertwined. Since novel biomarkers associated with HF that lead to these arrhythmogenic events are an area of unmet need, we aimed to identify the specific plasma Extracellular vesicles (EV)-driven microRNA cargo that could predispose ventricular cardiomyocytes to arrhythmia during HF as well as delineate targetable pathways to rescue the arrhythmic phenotype. We treated human pluripotent stem cell-derived ventricular cardiomyocytes (hPSC-VCM) with plasma-derived EVs from HF and control samples and observed significantly prolonged action potential duration in HF-treated hPSC-VCM (94.41 ± 16.13 msec) using optical voltage mapping. Small RNA cargo of the plasma EVs were sequenced to reveal 26 downregulated and 70 upregulated differentially expressed miRNAs between HF and control. Upon deconvolution analysis, many of these plasma miRNA transcripts were found to be enriched in the brain, RBCs, monocytes and other tissues. We also sequenced the long-RNA transcriptome of the recipient cardiomyocytes. We prioritized 33 targets for qRT-PCR validation based on predicted protein-coding targets of miRNA, and 10 of these mRNAs were different between HF and control EV-treated hPSC-VCMs. Interestingly, some mRNAs (EIF4E, NEDD4, ID3, ID1, CDKN1A, HSPD1) are known to be expressed during development. Pathway enrichment analysis of the validated targets converged in TGF beta signaling and Hippo pathways, implicated in cardiac developmental arrhythmogenic abnormalities. In conclusion, circulating EV small RNA cargo of HF patients can alter the electrophysiological properties of cardiomyocytes, many of which are derived, predominantly from the brain. More importantly, the arrhythmic phenotype is triggered when there is a recapitulation of developmental genes induced by the EV-derived miRNAs. While these miRNAs could be identified as putative biomarkers for SCD, targeting these developmental genes may be a fruitful therapeutic approach to rescue electrical remodeling in HF patients.
Abstract P2055: Long-term Elevation Of Cardiomyocyte Protein O-GlcNAc Levels Induces Cardiac Hypertrophy And Reduced Mitochondrial Function With Preserved Systolic Contractility
Authors: Chae-Myeong Ha, Sayan Bakshi, Manoja Brahma, Luke Potter, Samuel Chang, John C Chatham, Adam R Wende
Journal: Circulation Research (2023)

The severity and development of cardiovascular disease (CVD) can be affected by lifestyle and metabolic diseases, which can impact various mechanisms, including post-translational modifications (PTM). A specific PTM, known as protein O-linked β-N acetylglucosamine modification (O-GlcNAc), has been linked to both physiological responses and pathological progression of heart failure. This study was aimed to test whether sustained cardiac protein O-GlcNAc of proteins in cardiomyocytes contributes to cardiac adaptations or is sufficient to progress toward pathophysiology. Specifically, we generated transgenic mice overexpressing a naturally occurring dominant-negative O-GlcNAcase (dnOGA) in an inducible and cardiomyocyte-specific manner (dnOGAh). We induced dnOGA in male and female 8-10-weeks-old mice and examined the effects of 2-weeks (2wk) and 24-weeks (24wk) dnOGA overexpression, which resulted in a 1.8-fold increase in protein O - GlcNAc levels ( P &lt;0.01). The results showed that a 2wk increase in protein O-GlcNAc levels did not impact heart weight or function; however, 24wk of elevated protein O-GlcNAc led to cardiac hypertrophy (+19.8%, P &lt;0.01), fibrosis (M. Trichrome; +578%, P &lt;0.005), and diastolic dysfunction (E/A; +314%, P &lt;0.001). Despite several changes in gene expression associated with CVD, systolic function was maintained in 24wk dnOGA overexpression. mRNA-seq analysis revealed several gene signatures changed as early as 2wk of dnOGA that progressed at 24wk, including reduction of mitochondrial oxidative phosphorylation, fatty acid and glucose metabolism pathways (